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The JmjC oxygenases catalyze the N-demethylation of N(ε)-methyl lysine residues in histones and are current therapeutic targets. A set of human 2-oxoglutarate analogues were screened using a unified assay platform for JmjC demethylases and related oxygenases. Results led to the finding that daminozide (N-(dimethylamino)succinamic acid, 160 Da), a plant growth regulator, selectively inhibits the KDM2/7 JmjC subfamily. Kinetic and crystallographic studies reveal that daminozide chelates the active site metal via its hydrazide carbonyl and dimethylamino groups.

Original publication

DOI

10.1021/jm300677j

Type

Journal article

Journal

Journal of medicinal chemistry

Publication Date

11/07/2012

Volume

55

Pages

6639 - 6643

Addresses

Epigenetic Regulation of Chromatin Function Group, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K.

Keywords

Humans, Succinates, Plant Growth Regulators, Enzyme Inhibitors, Inhibitory Concentration 50, Protein Conformation, Substrate Specificity, Models, Molecular, Jumonji Domain-Containing Histone Demethylases